The invention relates to steroid esters and amides, . . . as well as their use as adjuvants for pharmacological studies and as pharmaceutical substances.
The invention relates to steroid esters and amides of formula I 
in which
R1 means a C1-C3 alkyl radical in xcex1- or xcex2-position,
Sk means xe2x80x94Cxe2x89xa1Cxe2x80x94(CH2)rxe2x80x94R2, (E) or (Z)xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)rxe2x80x94R2, xe2x80x94(CH2)2xe2x80x94(CH2)rxe2x80x94R2,
r means 1, 2 or 3,
R2 means xe2x80x94Oxe2x80x94(Xi1xe2x80x94Xi2xe2x80x94Xi3xe2x80x94 . . . xe2x80x94Xip)xe2x80x94R5, xe2x80x94C(xe2x95x90O)xe2x80x94(Yi1xe2x80x94Y12xe2x80x94Yi3xe2x80x94 . . . xe2x80x94Yip)xe2x80x94OR5, xe2x80x94OC(xe2x95x90O)R3, xe2x80x94NHC(xe2x95x90O)R3,
R3 means xe2x80x94Lxe2x80x94R4,
L means an n-membered, straight- or branched-chain alkylene group,
n, if St stands for an ABC-ring system of partial formula B, R1 stands for a methyl group in xcex1-position, Sk stands for a radical of formula xe2x80x94(CH2)3xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94Lxe2x80x94R4 and R4 stands for a hydrogen atom, n means an integer from 11 to 20; if St stands for an ABC-ring system of partial formula B, R1 stands for a C1-C2 alkyl radical in xcex2position, Sk stands for a radical of formula xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94Lxe2x80x94R4 and R4 stands for a hydrogen atom, n means an integer from 9 to 20; and in all other cases in which St stands for B, R2 stands for xe2x80x94OC(xe2x95x90O)R3 and R4 stands for a hydrogen atom, n means an integer from 5 to 20, or if St stands for an ABC-ring system of partial formula A, Sk stands for a radical of formula (E) or (Z)xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)rxe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94Lxe2x80x94R4 and R4 stands for a hydrogen atom, n means an integer from 5 to 20; if St stands for an ABC-ring system of partial formula A, Sk stands for a radical of formula xe2x80x94(CH2)2xe2x80x94(CH2)rxe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94Lxe2x80x94R4 and R4 stands for a hydrogen atom, n means an integer from 11 to 20 or if St stands for an ABC-ring system of partial formula C, R2 stands for xe2x80x94OC(xe2x95x90O)R3 and R4 stands for a hydrogen atom, n means an integer from 5 to 20; and in all other cases, n means an integer from 2 to 20,
p means an integer from 1 to 6,
R4 means hydrogen, xe2x80x94Oxe2x80x94(X11xe2x80x94Xi2xe2x80x94Xi3xe2x80x94 . . . xe2x80x94Xip)xe2x80x94R5, xe2x80x94C(xe2x95x90O)xe2x80x94(Yi1xe2x80x94Yi2xe2x80x94Yi3xe2x80x94 . . . xe2x80x94Yip)xe2x80x94OR5, xe2x80x94OR5, a C3-C10 cycloalkyl radical, xe2x80x94C(xe2x95x90O)R5a,
R5 means hydrogen, a C1-C10 alkyl radical,
R5a means hydrogen, a C1-C10 alkyl radical, a C1-C10 alkoxy radical,
Xi1 . . . p are the same or different and mean xe2x80x94[xe2x80x94C(O)xe2x80x94Wxe2x80x94NHxe2x80x94]xe2x80x94xe2x95x90X, and X as HOxe2x80x94Xxe2x80x94H is an xcex1-, xcex2- or xcex3-amino acid that is linked on its C-terminal end,
Yi1 . . . p are the same or different and mean xe2x80x94[xe2x80x94NHxe2x80x94Wxe2x80x94C(O)xe2x80x94]xe2x80x94xe2x95x90Y, and Y as Hxe2x80x94Yxe2x80x94OH is an xcex1-, xcex2- or xcex3-amino acid that is linked on its N-terminal end,
St represents one of the steroidal ABC-ring systems of partial formula A, B or C 
R6 means hydrogen, C1-C4 alkyl, halogen,
R7 means hydrogen, C1-C4 alkyl, halogen, and further an additional bond can be contained between carbon atoms 6 and 7 of ring systems A, B and C,
R8 means a group Z or an aryl radical optionally substituted several times by a group Z,
Z means hydrogen, halogen, xe2x80x94OH, xe2x80x94NO2, xe2x80x94N3, xe2x80x94CN, xe2x80x94NR9aR9b, xe2x80x94NHSO2R9, xe2x80x94CO2R9, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 acyloxy, C1-C10 acyl,
R9a,b are the same or different and have one of the meanings mentioned under R9,
R9 means hydrogen or C1-C10 alkyl and, if R9 is hydrogen, further their physiologically compatible salts with bases (Z=xe2x80x94CO2H) or acids (Z=xe2x80x94NR9aR9b)
The wavy lines that start from carbon atom 17 on the two substituents OH and Sk (side chain) mean that the respective substituent OH or Sk can be present both in xcex1-position and xcex2-position.
As alkyl groups R5, R5a, R6, R7, R8 and R9, straight-chain or branched-chain alkyl groups with 1-10 carbon atoms can be considered, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl as well as the appropriate unsaturated radicals (up to 3 double bonds), such as, for example, vinyl, propenyl, isopropenyl, butenyl, isobutenyl, butadienyl, hexenyl, etc.
Alkyl group R1 is a straight-chain or branched-chain alkyl group with 1-3 carbon atoms, namely a methyl, ethyl, propyl or isopropyl group.
Alkyl groups R5, R5a, R6, R7, R8 and R9 can be substituted by 1-3 halogen atoms, hydroxy groups, C1-C4 alkoxy groups, C6-C12 aryl groups, which can be substituted by 1-3 halogen atoms, heteroaryl radicals, such as furyl, benzofuryl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, further di-(C1-C4)-alkylamine and tri-(C1-C4)-alkylammonium. Possible alkyl groups are those mentioned above; those alkyl groups that are not substituted or are singly substituted are preferred. As substituents, there can be mentioned, for example, halogens, such as fluorine, chlorine or bromine atoms, phenyl, dialkylamines, such as dimethylamino, diethylamino, C1-C4 alkoxy, such as methoxy, ethoxy. The C6-C12 aryl groups can also be substituted by the halogen atoms fluorine, chlorine or bromine.
As preferred alkyl group R1, a methyl group can be cited, and as preferred alkyl groups R5, R5a, R6, R7, R8 and R9, those with 1-5 carbon atoms, such as, e.g., methyl, ethyl, propyl, isobutyl, butyl, tert-butyl can be mentioned.
Cycloalkyl groups R4 can contain 3-10, preferably 3-6 carbon atoms in the ring. Ring R4a can be substituted by straight-chain or branched alkyl groups with 1-4 carbon atoms. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopentyl, methylcyclohexyl can be mentioned.
Of side chains Sk that have the characteristic functional group R2, all lead to good results, but in particular an esterified {overscore (xcfx89)}-hydroxyprop-1-enyl and but-1-enyl chain as well as an esterified 3-hydroxypropyl chain are to be emphasized.
For radical R2, one of groups xe2x80x94Oxe2x80x94(Xi1xe2x80x94Xi2xe2x80x94Xi3xe2x80x94 . . . xe2x80x94Xip), xe2x80x94C(xe2x95x90O)xe2x80x94(Yi1xe2x80x94Yi2xe2x80x94Yi3xe2x80x94 . . . xe2x80x94Yip) or xe2x80x94OC(xe2x95x90O)R3 is preferred.
p preferably has the value 1, i.e., side chain Sk is then terminally esterified preferably with an amino acid or the carboxylic acid amide represents an amino acid.
The alkoxy groups that are contained in R5a, R8 or Z in general formula I are to contain 1 to 10 carbon atoms in each case, and methoxy, ethoxy, propoxy, isopropoxy and t-butyloxy groups are preferred.
In the C1-C10 acyl or C1-C10 acyloxy radical under definition Z, this is a C1-C10 alkanoyl(oxy) or benzoyl(oxy) radical, preferably a formyl, acetyl, propionyl or isopropionyl group.
Preferably one of the 17-substitutents in the compounds according to this invention stands for a free hydroxy group, as is evident from general formula I. It is also possible within the scope of this invention, however, that this free hydroxy group is etherified with one of the radicals mentioned under the definition of alkyl groups R5, R5a, R6, R7, R8 and R9 or is esterified with a C1-C10 acyl radical as mentioned under Z.
In the definitions for R6, R7 and Z, halogen means fluorine, chlorine, bromine or iodine.
If R8 is a group Z, this is preferably a dialkylamino group xe2x80x94NR9aR9b, especially the dimethylamino group, a C1-C10 alkoxy group, especially the methoxy group or a C1-C10 acyl radical, in particular the formyl or acetyl radical.
As an aryl radical R8 that is optionally substituted with a group Z, carbocyclic or heterocyclic aryl radicals, such as, e.g., phenyl, naphthyl, furyl, benzofuryl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, are suitable.
Preferred aryl radicals are phenyl, naphthyl, furyl, benzofuryl, thienyl, pyridyl; as substituted aryl radical R8, first of all the 4-cyanophenyl radical and a 4-halophenyl radical, especially the 4-fluorophenyl radical, can be cited.
In compounds that are preferred according to the invention, substituents R6 and R7 respectively stand for a hydrogen atom.
A Cxe2x80x94C single bond is preferably present between carbon atoms 6 and 7.
Amino acids HOxe2x80x94Xxe2x80x94H or Hxe2x80x94Yxe2x80x94OH can represent an xcex1-, xcex2- or xcex3-amino acid that is natural or unnatural, i.e., modified relative to their configuration or substitution.
Natural amino acids, such as, for example, glycine, alanine, valine, leucine, isoleucine, proline, are preferred.
A free amino group in HOxe2x80x94Xxe2x80x94H or Hxe2x80x94Yxe2x80x94OH can be provided with the protective groups that are familiar to one skilled in the art, such as, for example, tert-butyloxycarbonyl-(t-BOC), benzyloxycarbonyl, biphenylisopropyloxycarbonyl or 9-fluorenylmethoxycarbonyl.
The compounds below are especially preferred according to the invention:
(Z)-6xe2x80x2-(4-Cyanophenyl)-9,11xcex1-dihydro-17xcex2-hydroxy-17xcex1-[3-(1-oxopropoxy)-1-propenyl]-4xe2x80x2H-naphtho[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one
(Z)-6xe2x80x2-(4-cyanophenyl)-9,11xcex1-dihydro-17xcex2-hydroxy-17xcex1-[3-[(1-oxopentyl)oxy]-1-propenyl]-4xe2x80x2H-naphtho[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one
(Z)-6xe2x80x2-(4-cyanophenyl)-9,11xcex1-dihydro-17xcex2-hydroxy-17xcex1-[3-[(1-oxoheptyl)oxy]-1-propenyl]-4xe2x80x2H-naphtho[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one
(Z)-6xe2x80x2-(4-cyanophenyl)-9,11xcex1-dihydro-17xcex2-hydroxy-17xcex1-[3-[(1-oxononyl)oxyl-1-propenyl]-4xe2x80x2H-naphtho[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one
(Z)-6xe2x80x2-(4-cyanophenyl)-9,11xcex1-dihydro-17xcex2-hydroxy-17xcex1-[3-[(1-oxododecyl)oxy]-1-propenyl]-4xe2x80x2H-naphtho[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one
(Z)-6xe2x80x2-(4-cyanophenyl)-9,11xcex1-dihydro-17xcex2-hydroxy-17xcex1-[3-(1-oxo-2-methylpropoxy)-1-propenyl]-4xe2x80x2H-naphtho[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one
(Z)-6xe2x80x2-(4-cyanophenyl)-9,11xcex1-dihydro-17xcex1-[3-(3,3-dimethyl-1-oxobutoxy)-1-propenyl]-17xcex2-hydroxy-4xe2x80x2H-naphtho[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one
(Z)-6xe2x80x2-(4-cyanophenyl)-17xcex1-[3-(3-cyclopentyl-1-oxopropoxy)-1-propenyl]-9,11xcex1-dihydro-17xcex2-hydroxy-4xe2x80x2H-naphtho[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one
(Z)-6xe2x80x2-(4-cyanophenyl)-9,11xcex1-dihydro-17xcex1-[3-(1,4-dioxo-4-methoxybutoxy)-1-propenyl]-17xcex2-hydroxy-4xe2x80x2H-naphtho[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one
(Z)-6xe2x80x2-(4-cyanophenyl)-9,11xcex1-dihydro-17xcex1-[3-(1,4-dioxo-4-ethoxybutoxy)-1-propenyl]-17xcex2-hydroxy-4xe2x80x2H-naphtho[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one
(Z)-6xe2x80x2-(4-cyanophenyl)-9,11xcex1-dihydro-17xcex1-[3-(3-ethoxy-1-oxopropoxy)-1-propenyl]-17xcex2-hydroxy-4xe2x80x2H-naphtho[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one
(Z)-17xcex1-[3-[(aminoacetyl)oxy]-1-propenyl]-6xe2x80x2-(4-cyanophenyl)-9,11xcex1-dihydro-17xcex2-hydroxy-4xe2x80x2H-naphtho[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one
(Z)-6xe2x80x2-(4-cyanophenyl)-9,11xcex1-dihydro-17xcex1-[3-[[[[(1,1-dimethylethoxy),carbonyl]-amino] acetyl]oxy]-1-propenyl]-17xcex2-hydroxy-4xe2x80x2H-naphtho[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one
[S-(Z)]-17xcex1-[3-(2-amino-1-oxopropoxy)-1-propenyl]-6xe2x80x2-(4-cyanophenyl)-9,11xcex1-dihydro-17xcex2-hydroxy-4xe2x80x2H-naphtho[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one
[S-(Z)]-6xe2x80x2-(4-cyanophenyl)-9,11xcex1-dihydro-17xcex1-[3-[2-[[(1,1-dimethylethoxy)carbonyl]amino]-1-oxopropoxy]-1-propenyl]-17xcex2-hydroxy-4xe2x80x2H-naphtho[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one
[S-(Z)]-17xcex1-[3-(2-amino-3-methyl-1-oxobutoxy)-1-propenyl]-6xe2x80x2-(4-cyanophenyl)-9,11xcex1-dihydro-17xcex2-hydroxy-4xe2x80x2H-naphtho[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one
[S-(Z)]-6xe2x80x2-(4-cyanophenyl)-9,11xcex1-dihydro-17xcex1-[3-[2-[[(1,1-dimethylethoxy)carbonyl]amino]-3-methyl-1-oxobutoxy]-17xcex2-hydroxy-4xe2x80x2H-naphtho[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one
(Z)-9,11xcex1-dihydro-17xcex2-hydroxy-17xcex1-[3-(1-oxopropoxy)-1-propenyl]-6xe2x80x2-(3-pyridinyl)-4xe2x80x2H-naphtho[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one
(Z)-9,11xcex1-dihydro-17xcex2-hydroxy-17xcex1-[3-[(1-oxopentyl)oxy]-1-propenyl]-6xe2x80x2-(3-pyridinyl)-4xe2x80x2H-naphtho[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one
(Z)-9,11xcex1-dihydro-17xcex2-hydroxy-17xcex1-[3-[(1-oxoheptyl)oxy]-1-propenyl]-6xe2x80x2-(3-pyridinyl)-4xe2x80x2H-naphtho[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one
(Z)-9,11xcex1-dihydro-17xcex1-[3-(3,3-dimethyl-1-oxobutoxy)-1-propenyl]-6xe2x80x2-(3-pyridinyl)-17xcex2-hydroxy-4xe2x80x2H-naphtho[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one
(Z)-9,11xcex1-dihydro-17xcex1-[3-(1,4-dioxo-4-ethoxybutoxy)-1-propenyl]-17xcex2-hydroxy-6xe2x80x2-(3-pyridinyl)-4xe2x80x2H-naphtho[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one
[S-(Z)]-17xcex1-[3-(2-amino-1-oxopropoxy)-1-propenyl]-9,11xcex1-dihydro-17xcex2-hydroxy-6xe2x80x2-(3-pyridinyl)-4xe2x80x2H-naphtho[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one
[S-(Z)]-9,11xcex1-dihydro-17xcex1-[3-[2-[[(1,1-dimethylethoxy)carbonyl]amino]-1-oxopropoxy]-1-propenyl]-17xcex2-hydroxy-6xe2x80x2-(3-pyridinyl)-4xe2x80x2H-naphtho[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one
[S-(Z)]-9,11xcex1-dihydro-17xcex1-[3-[2-[[(1,1-dimethylethoxy)carbonyl]amino]-3-methyl-1-oxobutoxy]-1-propenyl]-17xcex2-hydroxy-6xe2x80x2-(3-pyridinyl)-4xe2x80x2H-naphtho[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one
(S)-17xcex2-[3-(2-amino-1-oxopropoxy)propyl]-11xcex2-[4-(dimethylamino)phenyl]-17xcex1-hydroxy-13xcex1-estra-4,9-dien-3-one
(S)-11xcex2-[4-(dimethylamino)phenyl]-17xcex2-[3-[2-[[(1,1-dimethylethoxy)carbonyl]amino]-1-oxopropoxy]propyl]-17xcex1-hydroxy-13xcex1-estra-4,9-dien-3-one
(S)-17xcex2-[3-(2-amino-3-methyl-1-oxobutoxy)propyl]-11xcex2-[4-(dimethylamino)phenyl]-17xcex1-hydroxy-13xcex1-estra-4,9-dien-3-one
(S)-11xcex2-[4-(dimethylamino)phenyl]-17xcex2-[3-[2-[[(1,1-dimethylethoxy)carbonyl]amino]-3-methyl-1-oxobutoxy]-1-propyl]-17xcex1-hydroxy-13xcex1-estra-4,9-dien-3-one
[S-(Z)]-17xcex1-[3-(2-amino-1-oxopropoxy)-1-propenyl]-11xcex2-[4-(dimethylamino)phenyl]-17xcex2-hydroxyestr-4-en-3-one
[S-(Z)]-11xcex2-[4-(dimethylamino)phenyl]-17xcex1-[3-[2-[[(1,1-dimethylethoxy)carbonyl]amino]-1-oxopropoxy]-1-propenyl]-17xcex2-hydroxyestr-4-en-3-one
[S-(Z)]-11xcex2-[4-(dimethylamino)phenyl]-17xcex1-[3-[2-[[(1,1-dimethylethoxy)carbonyl]amino]-3-methyl-1-oxobutoxy]-1-propenyl]-17xcex2-hydroxyestr-4-en-3-one
[S-(Z)]-4xe2x80x2-[17xcex1-[3-[2-[[(1,1-dimethylethoxy)carbonyl]amino]-1-oxopropoxy)-1-propenyl]-17xcex2-hydroxy-3-oxoestr-4-en-11xcex2-yl][1,1xe2x80x2-biphenyl]-4-carbonitrile
[S-(Z)]-4xe2x80x2-[17xcex1-[3-[2-[[(1,1-dimethylethoxy)carbonyl]amino]-3-methyl-1-oxobutoxy]-1-propenyl]-17xcex2-hydroxy-3-oxoestr-4-en-11xcex2-yl][1,1xe2x80x2-biphenyl]-4-carbonitrile
[S-(Z)]-9,11xcex1-dihydro-17xcex1-[3-[[[(1,1-dimethylethoxy)carbonyl]amino]acetyloxy]-1-propenyl]-17xcex2-hydroxy-6xe2x80x2-(3-pyridinyl)-4xe2x80x2H-naphtho[3xe2x80x2,2xe2x80x2,1xe2x80x2:10,9,11]estr-4-en-3-one
(S)-11xcex2-[4-(dimethylamino)phenyl]-17xcex2-[3-[[[(1,1-dimethylethoxy)carbonyl]amino]acetyloxy]propyl]-17xcex1-hydroxy-13xcex1-estra-4,9-dien-3-one
[S-(Z)]-11xcex2-[4-(dimethylamino)phenyl]-17xcex1-[3-[[[(1,1-dimethylethoxy)carbonyl]amino]acetyloxy]-1-propenyl]-17xcex2-hydroxyestr-4-en-3-one
[S-(Z)]-4xe2x80x2-[17xcex1-[3-[[[(1,1-dimethylethoxy)carbonyl]amino]acetyloxy]-1-propenyl]-17xcex2-hydroxy-3-oxoestr-4-en-11xcex2-yl][1,1xe2x80x2-biphenyl]-4-carbonitrile
[S-(Z)]-4xe2x80x2-[17xcex1-[3-[2-amino-3-methyl-1-oxobutoxy]-1-propenyl]-17xcex2-hydroxy-3-oxoestr-4-en-11xcex2-yl][1,1xe2x80x2-biphenyl]-4-carbonitrile.
The invention further relates to a process for the production of steroid esters and amides of general formula I, in which a compound of general formula II 
which has a terminal free hydroxyl group (R2xe2x80x2=OH) in side chain Skxe2x80x2 and in which all other substituents have the meaning indicated in general formula I and functional groups that are present in St optionally can be protected according to the way known to one skilled in the art, with an amino acid HOxe2x80x94Xxe2x80x94R5, optionally protected (R5xe2x89xa0H) on the amino group, or a peptide Hxe2x80x94Oxe2x80x94(Xi1xe2x80x94Xi2xe2x80x94Xi3xe2x80x94 . . . xe2x80x94Xip)xe2x80x94R5 (p greater than 1) or a carboxylic halide or anhydride (R3xe2x80x94C(xe2x95x90O)Hal (Hal=Cl, Br) or [R3xe2x80x94C(xe2x95x90O)xe2x80x94]2O, optionally protected on the amino groups, being esterified, or, if R2 in the compound of general formula I is to be a radicalxe2x80x94C(xe2x95x90O)xe2x80x94(Yi3xe2x80x94Yi2xe2x80x94Yi3xe2x80x94 . . . xe2x80x94Yip)xe2x80x94OR5, terminal hydroxy group R2xe2x80x2first oxidizes completely to the carboxyl group, then the carboxylic acid obtained, optionally after activation, is reacted with an amino acid R5xe2x80x94Yxe2x80x94OR5xe2x80x2, optionally protected (R5xe2x89xa0H) on the amino group, or a peptide R5xe2x80x94(Yi1xe2x80x94Yi2xe2x80x94Yi3xe2x80x94 . . . xe2x80x94Yip)xe2x80x94OR5 (p greater than 1), optionally protected on the amino group, or an optionally protected amine HNR5C(xe2x95x90O)R3 is reacted to the appropriate amide and optionally protective groups that are present in St, the amino acid, the peptide or the amine are cleaved.
All reaction steps necessary for this synthesis method (protection of the functional groups in St, protection of the amino group, esterification reaction, oxidation of the hydroxyl group, acid activation by formation of a xe2x80x9creactive ester,xe2x80x9d amide formation, cleavage of the protective groups) are performed according to methods that are standard and familiar to one skilled in the art.
If p is to have a value greater than 1 in the desired compound of general formula I, it can, instead of the peptide or amide, as described above, also be successively synthesized at the side chain by successive reaction steps on the side chain, for example, 
in which R5xe2x80x2, R5xe2x80x3 . . . are the same or different and represent R5 or H or an amino protective group and X1, X2, . . . have the meaning indicated above under Xi1 . . . p.
The starting compounds of general formula II that are used for the production of compounds of general formula I with a free hydroxy group in the 17-side chain Skxe2x80x2 (R2xe2x80x2=OH)xe2x80x94which are the compounds also designated elsewhere as xe2x80x9cinitial compoundsxe2x80x9dxe2x80x94as well as their production are described in a complete series of patents, patent applications and publications:
EP-A 0 129 499, EP-A 0259 248, EP-A 0 186 834, EP-A 0 447 014,
EP-A 0 116 974 EP-A 0 190 759, EP-A 0 147 361, EP-A 192 598, EP-A 0 283 428,
EP-A 0 404 283, WO-A 91/18917, WO-A 91/18918, WO-A 93/23020;
Steroids 44 (1984), 349
as well as other relevant bibliographic references known to one skilled in the art who is active in this field.
Many steroidal compounds, especially those with an lip-aryl radical, are partially very poorly soluble because of their substitution pattern, so that to preserve therapeutically relevant plasma levels, often superproportionally high single or multiple dosages or expensive formulation techniques must be used.
It has now been found, surprisingly enough, that the solubility of such compounds can be significantly improved if a free hydroxyl group is esterified or converted to an amide at a suitable point in the initial compound. In addition to improved solubility, the new compounds obtained therefore also possess increased biological action and selectivity compared to the corresponding initial compound.
Steroidal competitive progesterone antagonists, in which a free hydroxy group in the 17-side chain is esterified, are known already, for example, from the following European patent applications: a) 0 186 834, b) 0 283 428 and c) 0 404 283.
In case a), these are esters of the onapristone [11xcex2-(4-dimethylaminophenyl)-17xcex1-hydroxy-17xcex2-(3-hydroxypropyl)-13xcex1-methyl-4,9-gonadien-3-one], i.e., compounds with an ABC-ring system of partial formula B with alkyl radical R1 in xcex1-position and an esterified 17xcex1-(3-hydroxypropyl) side chain. The chain length of the acyl radical is limited to a maximum of 10 carbon atoms.
In case b), the compounds with an ABC-ring system reflect partial formula C and in case c), the compounds with an ABC-ring system have partial formula A, i.a., a 17-alkyl, 17-alkenyl or 17-alkinyl side chain, which can have, terminally, an optionally esterified hydroxy function.
Nothing is said in these publications on an improvement of the solubility of the initial compounds with a terminal, free hydroxy group in the 17-side chain by esterification of this same hydroxy group.
Based on the improved solubility (Tab. 1) of the compounds according to the invention, it is possible in principle to reduce the dose required for a pharmacologically desired effect, which generally leads to a reduction of undesirable side effects and thus to an expanded therapeutic range.
They are therefore suitable for the production of such pharmaceutical agents which can lead, in the case of equal molar dosage of a compound of general formula I such as the appropriate initial compound in an appropriate formulation, to a higher bio-availability of the active ingredient, or in which the dose of a compound of general formula I can be reduced relative to the initial compound to achieve a comparable biological effect.
The new compounds of general formula I are thus valuable pharmaceutical active ingredients. They have a strong affinity to the gestagen receptor and have a surprisingly large area of antigestagenic, antiglucocorticoidal, antimineral-corticoidal and antiandrogenic properties. These important biological actions can be used for medicinal purposes.
Active ingredients of this type with pronounced antigestagenic activity are suitable for inducing abortions, since they displace from the receptor the progesterone that is required to maintain pregnancy. They are therefore valuable and advantageous with respect to their use for postcoital birth control. The compounds of general formula I according to the invention are also suitable for the production of preparations for contraception for the female (WO-A 93/23020).
They can be used, moreover, for hormonal irregularities, for inducing menstruation and for inducing labor. Other types of indications in the field of gynecology are the treatment of symptoms that accompany a dysmenorrhea as well as endometriosis.
Finally, they can be used for the treatment of hormone-dependent carcinomas.
The compounds.of general formula I according to the invention also exhibit an antiglucocorticoidal activity and can thus also be used as pharmaceutical agents for treating corticoid-induced disorders (glaucoma) as well as for controlling side effects, which occur in the case of long-term treatment with glucocorticoids (Cushing""s Syndrome). They therefore also make it possible to control the disorders that are attributable to a hypersecretion of glucocorticoids, particularly adiposity, arteriosclerosis, hypertension, osteoporosis, diabetes as well as insomnia.
The compounds of general formula I according to the invention with antiandrogenic activity can be used in the treatment of hypertrophy and carcinoma of the prostate. They further make possible a specific treatment of androgenization symptoms in females: the pathological hairiness in the case of hirsutism, the androgenetic alopecia as well as the increased oil gland function in the case of acne and seborrhea can be affected advantageously.
The invention thus also relates to pharmaceutical agents based on the compounds of general formula I that are pharmaceutically compatible, i.e, nontoxic in the doses used, together with the usual adjuvants and vehicles.
Finally, this invention also relates to the use of the compounds of general formula I for the production of pharmaceutical agents.
The compounds according to the invention can be processed into pharmaceutical preparations for enteral, percutaneous, parenteral or topical administration according to methods of galenicals known in the art. They can be administered in the form of tablets, coated tablets, gel capsules, granulates, suppositories, implants, injectable, sterile aqueous or oily solutions, suspensions or emulsions, ointments, creams and gels.
In this connection, the active ingredient or active ingredients can be mixed with the adjuvants that are usual in galenicals, such as, e.g., gum arabic, talc, starch, mannitol, methyl cellulose, lactose, surfactants such as Tween or Myrj, magnesium stearate, aqueous or nonaqueous vehicles, paraffin derivatives, wetting agents, dispersing agents, emulsifiers, preservatives and flavoring substances for taste correction (e.g., ethereal oils).
A dosage unit contains about 0.1-100 mg of active ingredient(s). The dosage of the compounds according to the invention in humans is approximately 0.1-1000 mg per day.